Frequency and clinical consequences of extremely high maternal serum PAPP-A levels.

A multicentre study was carried out to determine the frequency and clinical consequences of extremely high maternal serum pregnancy-associated plasma protein (PAPP)-A. There was a total of 79 pregnancies with PAPP-A exceeding 5.0 multiples of the gestation-specific median in a series of 46 776 pregnancies tested (0.2%) at the 7 collaborating centres. Five pregnancies were lost to follow-up, one miscarried and one with Noonan's syndrome was terminated. Of the remaining 72 that ended in a live birth, one infant had gastroschisis and five pregnancies had obstetric complications: pre-eclampsia, pregnancy-induced hypertension, gestational diabetes and two with growth retardation. Among women with high PAPP-A and no complications or adverse outcomes, there was no evidence of a substantial change in the levels of other Down syndrome markers or the extent of nuchal translucency. Three analytical methods were used to assay PAPP-A and yielded different frequencies of extremely high levels (0.05%, 0.4% and 0.6%) possibly owing to cross-reaction with another substance. We conclude that women with high PAPP-A can be reassured that there is no reason to suppose that the outcome of pregnancy will differ from those with normal levels, provided other markers are normal. If, as more centres move their Down syndrome screening practice to the first trimester, additional cases emerge with Noonan's syndrome or gastroschisis and raised PAPP-A, this advice will need to be modified.

Maternally inherited hearing impairment in a family with the mitochondrial DNA A7445G mutation.

Despite the increasing number of reports of families with hearing impairment and mitochondrial DNA (mtDNA) mutations, the frequency of these mutations as causes of non-syndromic sensorineural hearing impairment (NSSHI) remains unknown. Mutations such as A1555G, A7445G and 7472insC have been found in several unrelated families implying they are more frequent than initially thought. We describe a family with NSSHI due to the presence of the homoplasmic mtDNA A7445G mutation in the tRNASer(UCN) gene. This is the fourth such family described with this mutation, all of different genetic backgrounds. Our study also demonstrates the difficulties sometimes encountered in establishing mitochondrial inheritance of hearing impairment in some families.

Familial Down syndrome: evidence supporting cytoplasmic inheritance.

The frequently observed familial aggregation of Down syndrome (DS) 47,+21 and other aneuploidies and the phenomenon of double aneuploidy involving DS cannot be accounted for by chance alone. To clarify possible aetiological factors, pedigrees from all 7 affected families with repeated marriages referred to two regional genetics centres were examined. In each case the recurrence of aneuploidy was on the mother's side (p<0.01). Such a pattern suggests cytoplasmic inheritance of a risk factor. The hypothesis that mitochondrial DNA mutations have a role in the aetiology of DS is supported by other observations as well as by theoretical considerations.

The genetic legacy of Paleolithic Homo sapiens sapiens in extant Europeans: a Y chromosome perspective.

A genetic perspective of human history in Europe was derived from 22 binary markers of the nonrecombining Y chromosome (NRY). Ten lineages account for >95% of the 1007 European Y chromosomes studied. Geographic distribution and age estimates of alleles are compatible with two Paleolithic and one Neolithic migratory episode that have contributed to the modern European gene pool. A significant correlation between the NRY haplotype data and principal components based on 95 protein markers was observed, indicating the effectiveness of NRY binary polymorphisms in the characterization of human population composition and history.

[The use of oxidant-antioxidant system indices in forming groups at high genetic risk]. / Ispol'zovanie pokazatelei oksidantno-antioksidantnoi sistemy pri formirovanii grupp vysokogo geneticheskogo riska.

While studying the pathogenetic mechanisms of Down syndrome, the imbalance of oxidant-antioxidant system in donors of extrachromosome 21 was detected. This fact was a basis for screening of new prenatal biochemical markers of Down syndrome. The ratio of free radical processes intensity and SOD activity was found as most informative index reflecting the state of oxidant-antioxidant system. It was proposed as additional criterion for the formation of high risk groups to increase the efficiency of prenatal diagnostics of Down syndrome.

[The prenatal diagnosis of Down's syndrome based on the biochemical screening of maternal serum markers]. / Prenatal'naia diagnostika sindroma Dauna na osnove biokhimicheskogo skrininga markerov materinskoi syvorotki.

The role of maternal alpha-fetoprotein and chorionic gonadotprin screening in complex prenatal diagnosis of Down syndrome had been studied. The average markers' values in cases of fetus trisomy 21 were 0.67 MoM (AFP) and 2.68 MoM (HGG). The correlative dependence between the markers' levels in trisomy 21 and the date of testing have been found. The high efficiency of differentiative approach to invasive investigations in the older age group of pregnant (above 35 years old) on the basis of AFP and HGG screening has been established.

[The biochemical marker dynamics of the maternal serum in different chromosomal disorders of the fetus]. / Dinamika biokhimicheskikh markerov materinskoi syvorotochki pri razlichnykh khromosomnykh narusheniiakh u ploda.

The reasons for false-positive results of Down syndrome screening have been analysed. It has been found that the family pericentric inversions of chromosome 9 in fetus are accompanied by AFP and HCG changes equal to Down syndrome pregnancies. The average marker's levels in cases of per inv (9) were: AFp-0.51 MoM, HCG-3.71 MoM. The dynamics of markers in amniotic fluid has been studied. Clinical significance of per inv (9) in medicogenetic consultation were discussed.

[The age-dependent incidence of Down's syndrome and the free-radical theory]. / Vozrastzavisimaia chastota sindroma Dauna i svobodnoradikal'naia teoriia.

Age-dependent distribution of Down syndrome frequency in the light of free-radical theory of aging was carried out in this work. The frequency of Down syndrome had been analysed during the period of 1990-1995. The investigation of radical process intensity was performed in the group of women of child-bearing age by the chemoluminescence method. It has been demonstrated that the age of a woman is one of the main reasons both of Down syndrome frequency increase and free radical accumulation. The obtained analogy between age-dependent distribution of Down syndrome frequency and age-dependent accumulation of free radicals is one more argument for the role of free radicals in the pathogenesis of Down syndrome.

[Free radicals in the origin and clinical manifestation of Down's syndrome]. / Svobodnye radikaly v vozniknovenii i klinicheskom proiavlenii sindroma Dauna.

The high level of free radicals and antioxidant protection disbalancing cause the chromosome nondisjunction in meiosis, appearance of trisomy 21 and fetuses with Down's syndrome, age-dependent pathology, of parent's mosaic clone, clinical manifestations of the syndrome, diseases in relatives, recurrent cases of trisomy 21. The comparative analysis of clinical traits of Down's syndrome and pathological changes in families with after-effects of radiation exposure was carried out. The factors causing an increase in the level of free radicals were considered.

[The formation of risk groups and the performance of invasive prenatal diagnosis]. / Formirovanie grupp riska i provedenie invazivnoi prenatal'noi diagnostiki.

The results of the formation of women risk groups for invasive methods of prenatal diagnosis and cytogenetic investigations of amniotic fluid are presented. It was shown that the efficiency of prenatal diagnosis was increased due to the complex use of ultrasonography, screening for alpha-fetoprotein and chorionic gonadotropin, and invasive methods of prenatal diagnosis.

[The use of the screening of maternal serum factors for the prenatal diagnosis of fetal developmental defects and chromosomal diseases]. / Ispol'zovanie skrininga faktorov materinskoi syvorotki dlia prenatal'noi diagnostiki porokov razvitiia i khromosomnykh zabolevanii ploda.

The association of the levels of alpha-fetoprotein and chorionic gonadotropin with congenital developmental defects and chromosomal abnormalities of fetus was studied. The correlation of elevated level of alpha-fetoprotein with defects of neuraxis, kidney and abdominal wall of fetus was shown. These data are used for screening of women with a high risk for Down's syndrome and other chromosomal abnormalities.

[The role of mitochondrial DNA in the origin of regular trisomy 21]. / O roli mitokhondrii DNK v proiskhozhdenii reguliarnoi trisomii khromosomy 21.

Hypothesis about cytoplasmic heredity and the influence of mitochondrial DNA mutations on the pathogenesis of 21 trisomy has been suggested. It explains the association of increased risk of trisomy with the maternal age, malignant diseases, autoimmune processes, other pathologies and with the origin of paternal 21 chromosome.

[Individual variability in the level of spontaneous sister chromatid exchanges]. / Individual'naia variabel'nost' urovnia spontannykh sestrinskikh khromatidnykh obmenov.

The contribution of genetic factors to spontaneous level of the sister chromatid exchanges (SCE) has been determined on the basis of the twin method of study. A close relation is shown to exist between the SCE tests in the group of the monozygotic twins which is a result of the common genotype. The SCE test with late BUdR introduction is under rigid genetic control.